Brooke S. Rambally

Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer

We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki‐67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate‐activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamycin (mTOR) pathway were measured by immunohistochemistry. Global, untargeted metabolomics analysis of serum pre‐ and postmetformin treatment, and matched tumor, was performed. Metformin reduced proliferation by 11.75% (P = 0.008) based on the comparison of pre‐ and posttreatment endometrial tumors. A total of 65% of patients responded to metformin as defined by a decrease in Ki‐67 staining in their endometrial tumors post‐treatment. Metformin decreased expression of phosphorylated (p)‐AMPK (P = 0.00001), p‐Akt (P = 0.0002), p‐S6 (51.2%, P = 0.0002), p‐4E‐BP‐1 (P = 0.001), and ER (P = 0.0002) but not PR expression. Metabolomic profiling of serum indicated that responders versus nonresponders to treatment were more sensitive to metformins effects on induction of lipolysis, which correlated with increased fatty acid oxidation and glycogen metabolism in matched tumors. In conclusion, metformin reduced tumor proliferation in a pre‐operative window study in obese EC patients, with dramatic effects on inhibition of the mTOR pathway. Metformin induced a shift in lipid and glycogen metabolism that was more pronounced in the serum and tumors of responders versus nonresponders to treatment.This study provides support for therapeutic clinical trials of metformin in obese patients with EC.

Displaced granulosa cells in the fallopian tube mistaken for metastatic granulosa cell tumor.

A 44-yr-old woman underwent a total hysterectomy and bilateral salpingectomy secondary to uterine leiomyomas. Gross examination of the fallopian tubes revealed no masses or lesions; however, 2 small foci of granulosa cells were identified microscopically within one of the fallopian tubes. These foci were suspicious for granulosa cell tumor metastases. The patient subsequently underwent a bilateral oophorectomy, which revealed no primary granulosa cell tumor. Immunohistochemical studies were used to help support the benign nature of the granulosa cells within the fallopian tube. A review of the literature revealed only 1 similar case report of displaced benign granulosa cells within the fallopian tubes. The ovaries in both this case and the previous case report were found to contain multiple cystic follicles, suggesting ovulation as the likely mechanism of displacement. Knowledge of this rare occurrence and the use of immunohistochemical staining are paramount to making a correct diagnosis, thus preventing a misdiagnosis of malignancy and possible unnecessary treatment.

Circulating Blasts and Associated Hematologic Disorders in Neonates with Down Syndrome

We analyzed complete blood count (CBC) data obtained from neonates with Down syndrome (DS) in a primarily Hispanic population over a 10-year period to determine the incidence of hematologic abnormalities and the relationship of abnormalities to the presence of circulating blasts (CB). Hematologic values obtained during the first 10 days were analyzed. Definitions were: CB, ≥ 1% blasts manually counted on peripheral smear; elevated white blood cell count (WBC), >30,000 cells/mm(3); thrombocytopenia, platelet count < 150,000/mm(3); polycythemia, hematocrit >65%. Two hundred thirty-two neonates (88% Hispanic) with DS had 692 CBCs available for analysis. The presence of CB (11.6%) and the incidence of thrombocytopenia (60.2%) were significantly higher in DS neonates than in the reference group. Elevated WBC (33.3%) and thrombocytopenia (84.6%) were more common in DS neonates with CB versus those with no CB. No relationship between thrombocytopenia and polycythemia was observed. Unlike previous reports, we did not observe a male predominance in those DS neonates with CB. Thrombocytopenia occurred frequently in DS neonates and was significantly more likely in those with CB than in those with no CB. CBC screening should be performed routinely in DS neonates.

Predicting neonatal respiratory morbidity by lamellar body count and gestational age.

Abstract Aims: To develop a predictive model for assessing the risk of developing neonatal respiratory morbidity using lamellar body counts (LBCs) and gestational age (GA) to provide a more patient-specific assessment. Methods: Retrospective cohort study of patients’ ≥32 weeks’ gestation who received amniocentesis with LBC analysis over a 9-year period. Respiratory morbidity was defined as respiratory distress syndrome, transient tachypnea of the newborn or oxygen requirement for >24 h. Logistic regression analyses were used to predict the absolute risk and odds of respiratory morbidity as a function of GA and lamellar body count. Results: Two hundred and sixty-seven mother-infant pairs included in the analysis with 32 cases (12.0%) of respiratory morbidity. When compared to those without respiratory morbidity, neonates with respiratory morbidity had amniocentesis performed at an earlier median GA, had lower mean birthweight and had lower median LBC (P<0.01). The GA specific absolute risks and odds ratios for the presence of respiratory morbidity were calculated. The predicted absolute risks of neonatal respiratory morbidity ranged from 38% at 32 weeks to 6% at 40 weeks when LBC were 35,000/μL. Conclusion: GA specific predicted risk of neonatal respiratory morbidity using LBC provides a statistical model, which can aid clinicians in individually counseling patients regarding the absolute risk of their neonate developing respiratory morbidity.